P368: GENOMIC LANDSCAPE OF PEDIATRIC ACUTE B LYMPHOBLASTIC LEUKEMIA IN CHINA
Authors: Yangyang Gao, Xiaofan Zhu, Xiaojuan Chen
Journal: HemaSphere (2023)

Background: With the application of next generation sequencing (NGS) technology, genomic analysis has been widely performed in children with acute lymphoblastic leukemia (ALL), promoting our deeper understanding of genetics and helping us to explore the correlation between gene mutations and clinical characteristics, early treatment response and long-term prognosis. Aims: To characterize the mutational spectrum of acute B lymphoblastic leukemia (B-ALL) in children at first diagnosis and analysis its impact on overall survival (OS) and event free survival (EFS). Methods: A total of 349 children who were newly diagnosed with B-ALL and treated with CCCG-ALL2015 protocol in Blood Disease Hospital, Chinese Academy of Medical Sciences were enrolled in this study. Targeted sequencing and analysis of 267 hematological tumor-related genes were performed based on NGS. The impact of gene mutation on patients’ OS and EFS was analyzed through Kaplan-Meier and Cox regression methods. Results: A total of 157 different gene mutations were detected in 336 (96.3%) of 349 children. KRAS (76/349,21.8%) was the most common mutant gene, followed by NRAS (75/219,21.5%), FAT1(71/349,20.3%), KMT2D (71/349,20.3%), CREBBP (47/34913.5%), FLT3(42/349,12.0%). Mutated genes were associated with several functional pathways. Signal transduction (27.8%), transcription factor (20.1%) and epigenetic modification (18.3%) pathway mutations were common. The correlation between gene mutation and clinical features was analyzed. Patients with ASXL1 mutations had a higher white blood cell count (26.79vs7.86*109/L, P=0.006), but those with CREBBP (9.71vs4.75*109/L, P=0.001) or PTPN11(8.83vs4.98*109/L, P=0.029) mutations had a lower white blood cell count. PLCG2 mutated patients had a higher incidence of extramedullary infiltration (33.3%vs7.4%, P=0.008). Patients with JAK2(42.9%vs16.6%, P=0.030), JAK3(41.7%vs16.8%, P=0.042) and IKZF1(55.6%vs16.6%, P=0.010) mutations at diagnosis had higher incidence of minimal residual disease (MRD) level on day 46 is greater than or equal to 0.01%. We further analyzed the influence of gene mutation on prognosis (Figure1), and found JAK3(3-year OS: 68.2%vs96.0%, P=0.016), KRAS (90.0%vs97.9%, P=0.020) or KMT2C (83.6%vs96.4%, P=0.026) mutation had negative impacts on OS. According to multivariate analysis, JAK3 mutation was recognized as an independent prognostic factor for OS. Univariate and multivariate analysis on EFS showed that gene mutations of JAK3, KDM6A and SH2B3 were independent influencing factors of EFS. JAK3 (3-year EFS:58.3%vs85.0%, P=0.002), KDM6A (58.3%vs84.9%, P=0.013) or SH2B3(32.4%vs85.8%, P<0.001) mutation was associated with worse EFS. The EFS of patients with KRAS (77.6%vs85.8%, P=0.060) mutation was lower than those without KRAS mutation, but the difference was not statistically significant. The 3-year OS was 95.8%, and the 3-year EFS was 84.1% for all 349 children. Summary/Conclusion: Gene mutation is common in pediatric acute B lymphoblastic leukemia, especially the RAS signal pathway related gene mutation. Gene mutations involve multiple signaling pathways. Prognostic analysis finds that multiple gene mutations are associated with prognosis. JAK3 gene mutation is usually a strong predictor of poor prognosis.Keywords: Acute lymphoblastic leukemia, B cell, Children